tbuckley/cabot-search huggingface dataset:
Analytic Approaches to Clinical Validation of Results From Preclinical Models of Glioblastoma: A Systematic Review
Authors: Beth Fitt, Grace Loy, Edward Christopher, Paul Brennan, Michael T C Poon
Journal: Neuro-Oncology (2022)

Abstract AIMS Analytic approaches to clinical validation of results from preclinical models are important in assessment of their relevance to human disease. This systematic review examined consistency in reporting of glioblastoma cohorts from The Cancer Genome Atlas (TCGA) or Chinese Glioma Genome Atlas (CGGA) and assessed whether studies included patient characteristics in their survival analyses. METHOD We searched Embase and Medline on 02Feb21 for studies using preclinical models of glioblastoma published after Jan2008 that used data from TCGA or CGGA to validate the association between ≥1 molecular marker and overall survival in adult patients with glioblastoma. Main data items included cohort characteristics, statistical significance of the survival analysis, and model covariates. RESULTS There were 58 eligible studies from 1,751 non-duplicate records investigating 126 individual molecular markers. In 14 studies published between 2017 and 2020 using TCGA RNA microarray data that should have the same cohort, the median number of patients was 464.5 (interquartile range 220.5–525). Of the 15 molecular markers that underwent more than one univariable or multivariable survival analyses, five had discrepancies between studies. Covariates used in the 17 studies that used multivariable survival analyses were age (76.5%), pre-operative functional status (35.3%), sex (29.4%) MGMT promoter methylation (29.4%), radiotherapy (23.5%), chemotherapy (17.6%), IDH mutation (17.6%) and extent of resection (5.9%). CONCLUSION Preclinical glioblastoma studies that used TCGA for validation did not provide sufficient information about their cohort selection and there were inconsistent results. Transparency in reporting and the use of analytic approaches that adjust for clinical variables can improve the reproducibility between studies.
Evaluation of a Panel of 105 Cytokines from Human Glioblastoma (GBM) Tissue Maintained, and Treated, on a Unique Microfluidic Platform
Authors: Amr Moursi, Antonia Barry, Shailendra Achawal, Chittoor Rajaraman, Lauric Feugere, Pedro Beltran-Alvarez, John Greenman
Journal: Neuro-Oncology (2022)

Abstract AIMS The first aim was to measure the changes in the levels of 105 cytokines potentially released by GBM tissue maintained on-chip. The second aim was to compare the cytokine profiles from control GBM tissue and tissue treated with anti-GBM drugs {temozolomide (TMZ) at 1 and 10μM both with 1μM arginine methylation inhibitors}. METHOD Intra-operative tissue biopsies were taken from the tumour and transferred immediately from the operating theatre to Hull University laboratories (&amp;lt; 1 hour). Tissue samples were maintained in a viable state in a bespoke chip device for eight days. The biopsy was perfused (3μl/min) with culture medium, with or without drug treatment. Eﬄuents from the biopsies were collected at 24h intervals. Cytokines levels were measured using the Proteome Profiler Human XL Cytokine Array Kit (R&amp;D Systems), each membrane is spotted with 105 different cytokine antibodies in duplicate. RESULTS Six GBM diagnosed patients (five negative for MGMT) were recruited and studied. Eleven cytokines showed consistent, high level, release from GBM tissue either in control or treated samples: Chitinase3-like1, IL8(CXCL8) ,MCP-1(CCL2 ),MIF(Macrophage migration inhibitory factor), MMP-9(Matrix metallopeptidase 9), Osteopontin(OPN), Serpin E1, VEGF(Vascular endothelial growth factor) ,Apolipoprotein A-I, Angiogenin and Emmprin. Multivariate analysis (PERMANOVA) did not show evidence for differential cytokine release profiles with time (P=0.113), treatment (P=0.629), , nor the combined interaction (P=0.936). CONCLUSION GBM biopsies remained viable on the microfluidic platform, shown by sustained cytokine production cytokines. We have also shown that treatment with TMZ plus arginine methylation inhibitors does not significantly affect cytokine release over an eight day period.
Coping Better Together
Authors: Alison Rodway
Journal: Neuro-Oncology (2022)

Abstract AIMS Coping Better Together is a patient education course that is offered by The Walton Centre for brain tumour patients following surgery. The diagnosis and treatment of brain tumours impacts patients and families long past the time of diagnosis, surgery and adjuvant treatment. The Coping Better Together Course recognises the impact on health and wellbeing and aims to equip patients and families with information, strategies and resources that improve quality of life. METHOD The course comprises of education sessions from a wide range of health care professionals, consultants, clinical nurse specialists and allied health care professionals. It provides opportunity for networking allowing patients and families to meet with others facing similar difficulties. Prior to the impact of the Covid pandemic this course was run off site and solely in person. The impact of Covid has brought the course within The Walton Centre allowing for both face to face attendance and virtual access, thus making it more accessible. RESULTS Feedback from the day is highly favourable and valued by those who attend. Patients and families report that they receive valuable information and go away better equipped in dealing with both symptoms and living with the effects of their diagnosis. CONCLUSION This in house CNS led patient education course has an impact on quality of life and improves patient experience. The course provides a framework that can be easily utilised, followed and adapted by other healthy care professionals in providing education and support to brain tumour patients and their families.
The Cost of Treating Adult Glioblastoma Patients in England
Authors: Nour Kanso, Radvile Mauricaite, Kerlann Le Calvez, Matt Williams
Journal: Neuro-Oncology (2022)

Abstract AIMS The GlioCova dataset uses linked English national cancer data on all 51,775 adult primary brain tumour patients diagnosed between 2013-2018, of which 15,277 patients were diagnosed with a cranial glioblastoma. Here we present data on the direct care costs of treatment, based on secondary care data. METHOD We examined data on inpatient and outpatient care for all cranial glioblastoma patients in the dataset. We used the NHS HRG4+ Reference Costs Grouper 2017-2018 to assign costs standardised to 2017-2018. RESULTS A total of 14,999 patients were admitted to hospital between the last three months of 2012 and up to the end of 2019, of which we were able to assign costs to 14,691 patients. Total inpatient cost was over £321 million (34% of which was attributed to direct costs of spells of neurosurgery, chemotherapy, and radiotherapy). 14,528 patients had outpatient care, of which we were able to assign costs to 14,419 patients. Total outpatient cost was over £92 million (41% of which was attributed to chemotherapy and radiotherapy). CONCLUSION The estimated secondary care costs for adult glioblastoma patients in England were over £414 million for patients diagnosed between 2013-2018, but do not include patient out-of-pocket costs, primary care, social care, or end of life care costs. Future work will examine variation in care and costs and extend it to the wider brain tumour cohort. We also hope these data will help make the economic argument for improvements in care for brain tumour patients. More information on GlioCova: https://blogs.imperial.ac.uk/gliocova/about-gliocova/
Development of Novel LAT1 Targeting Small Molecules for Boron Neutron Capture Therapy (BNCT) and Potential Application for Treating Glioblastoma
Authors: Kendall Morrison
Journal: Neuro-Oncology (2022)

Abstract AIMS to make molecules that deliver more Boron than BPA for boron neutron capture therapy BNCT METHOD Boronated compounds were designed based on known LAT-1 substrates, synthesized using boronation techniques and purified using preparative HPLC. The compounds were formulated to achieve high concentrations when compared to BPA-fructose (BPA-F). Boronated compounds were tested for boron uptake and retention in multiple cell lines expressing either LAT1 and/or PEPT1. Compounds were further tested in multiple human xenograft models representing the cancer indication currently treatable by BNCT as well as in one syngeneic colon tumor model that may have high PEPT1 expression. Intracellular and intra tumor boron concentration were measured by ICP OES. We also synthesized 2 dipeptides and tested them in BNCT experiments with our collaborators at Kyoto University in Japan. They were tested in a CT26 mouse syngeneic model using neutrons from KURR1. RESULTS We synthesized multiple boronated compounds with better solubility than BPA (100 mg/ml v 30mg/ml in fructose). They were readily taken up in multiple cell lines and one of these compounds had longer retention than others. In competition experiments we were able to show that this compound was a superior substrate for LAT1. We also showed better BNCT results with our molecules compared to BPA. CONCLUSION BPA works for BNCT but it has limitations such as poor solubility. We made several new boronated compounds with better solubility than BPA and showed that we could deliver 2-3 x more boron in vitro and in vivo and better BNCT outcomes at KURR1.
COVID-19 Pandemic Neuro-Oncology Consultation Settings: Ensuring Services Address Patient Preferences
Authors: Joao Galante, Aaron Ben-Joseph, Samantha Forner, Elaine Kennaird, Meeta Durve, Jennifer Glendenning
Journal: Neuro-Oncology (2022)

Abstract Aims The Covid-19 pandemic expanded the use of virtual consultations (telephone (T) or video (V)). Moving forward, Neuro-Oncology consultation settings require tailoring to optimally meet patient needs. This project aimed to evaluate patient perceptions of consultation settings to optimise service planning and ongoing incorporation of T and V options for patients with high grade brain tumours. METHOD From February 2022, patient perceptions on consultation settings were prospectively sought on follow-up/on- treatment appointments in Kent Oncology Centre. The peer-reviewed anonymised survey explored rationale for consultation setting, travelling (time, distance and arrangements) , satisfaction with appointment parameters (amount/ clarity of information, patient perception of support, assessment of symptoms and ability to ask questions) and setting preferences moving forward. RESULTS The majority of consultations were F2F, 1/3 had teleconsultations. 2/5 of patients were given a choice of consultation setting. Reason for teleconsultation included geographical distance, longer journey time, consultant decision, disability, work and active Covid-19 infection. All settings recorded good levels of satisfaction, however the majority (&amp;gt;2/3) would recommend F2F appointments to others for scan results, pre-chemotherapy/on-radiotherapy checks, specialist nurse reviews and end of treatment reviews. CONCLUSION Despite reassuring levels of satisfaction for both F2F and non-F2F appointments, F2F setting remains preferred regardless of the aim of the consultation. For a selected number of patients, teleconsultation has advantages due to geographical constraints, however the option of F2F consultations remains important and patients should be involved in these decisions.
Motor Seizures Confer Overall Survival Benefit in WHO Grade 2 Glioma
Authors: Sam Fairclough, Ryan Mathew, John Goodden, Paul Chumas, Melissa Maguire
Journal: Neuro-Oncology (2022)

Abstract AIMS The prevalence of epilepsy in WHO grade 2 glioma is high, with seizures often being the presenting symptom. We explore the epidemiology of seizures in this patient population in a regional neurosurgical centre. METHOD Electronic health records of patients with histologically-proven WHO grade 2 glioma (n=227) were reviewed with data collected including patient demographics, epilepsy prevalence and seizure semiology. Relationships between epilepsy and overall survival were calculated using a Cox proportional hazards model in the statistical software “R,” controlling for all other variables – including histological diagnosis. RESULTS Overall, 196/227 (86.3%) patients were diagnosed with epilepsy - either at presentation (179/196, 91.3%), or during the course of their disease (17/196, 8.7%) . Mean follow-up was 7.0 years. Diffuse astrocytoma histology was associated with reduced overall 10-year survival (HR 4.68, p&amp;lt;0.001) compared with oligodendroglioma. The majority of patients experienced focal onset seizures (n=118) as their predominant seizure type, with generalised (n=64) and unknown onset seizures (n=14) less likely. Almost two-thirds (64.8%) of those with epilepsy had experienced at least one generalised tonic-clonic seizure. During seizures, loss of awareness (n=132) and presence of motor activity (n=147) were frequently encountered. Predominantly experiencing seizures without any motor activity also appeared to confer poorer survival outcomes (HR 2.39, p&amp;lt;0.05), even when controlled for histology. CONCLUSION Most WHO Grade 2 glioma patients experience focal seizures, though generalised tonic-clonic seizures are common. Motor seizure activity is a frequent feature in WHO Grade 2 glioma and may confer a survival benefit, when compared to patients that have primarily non-motor seizure activity.
Redefining a Rare CNS Tumour Through Targeted Genetic Sequencing
Authors: Hazem Abuhusain, Veejay Bagga
Journal: Neuro-Oncology (2022)

Abstract AIMS Isolated cerebellar vermis lesions in adults is a rare location and entity with few literature case reports detailing gangliogliomas and gangliocytomas. Using targeted genetic sequencing, traditional histological diagnosis can be refined further, with a clear impact on prognosis as well as possible genetic counselling implications. METHOD A single case of cerebellar vermis lesion, identified incidentally through imaging of a neck nodule, with subtle features of ataxia and mild impairment of initiation of speech. Sub-total resection of lesion underwent standard histopathological work-up, followed by targeted genetic sequencing to obtain an integrated diagnosis. RESULTS Histological assessment identified atypical ganglion cells labelled with Synaptophysin on immunohistochemistry. Features closely resembled dysplastic cerebellar gangliocytoma (Lhermitte-Duclos Disease). Further targeted sequencing showed no evidence of IDH1, IDH2, TERT promoter, or histone mutation, however, BRAF mutation was present, supporting an alternate diagnosis of ganglioglioma. CONCLUSION Precision medicine is facilitated with advanced diagnostic techniques. This redefines categorisation of some CNS tumours, particularly rare entities. Techniques are especially valuable to individual patient management as they can have a direct impact on aspects of clinical work-up, prognosis, follow-up, and in some cases, genetic counselling.
First Line Treatment of Adult Glioblastoma Patients in England 2103-2018 from the GlioCova Project
Authors: Kerlann Le Calvez, Radvile Mauricaite, Matt Williams
Journal: Neuro-Oncology (2022)

Abstract AIMS The Gliocova dataset uses linked English national cancer data on all 51,775 adult primary brain tumour patients diagnosed between 2013-2018. Here we present detailed analysis of first-line treatments of adult glioblastoma (GBM) patients. METHOD We identified all adults patients diagnosed with a GBM. We focused on the first line of treatment and we defined ‘maximal’ first-line treatment as surgical resection followed by chemo-radiotherapy with 59-60 Gy and with at least one cycle of adjuvant chemotherapy Temozolomide. RESULTS 15,294 patients were diagnosed with a glioblastoma (60% male) with a median age of 66. 79% of patients received some treatment, with younger patients more likely to be treated (&amp;gt;90%, 18 - 59; &amp;lt; 30%, &amp;gt; 80). 54% underwent debulking surgery; 23%, biopsy. 14% received ‘maximal’ treatment and 21%, none. Patients who had no treatment had a median survival of 2 months whereas patients who received ‘maximal’ treatment had a median survival of 16 months. CONCLUSION Most adult patients with a GBM in England have a histological diagnosis, and some oncological treatment. However, only 14% receive ‘maximal’ treatment. Of the 3222 patients who received none, some of these may have had purely private treatment; however, our dataset includes any private sector work undertaken in NHS hospitals. Survival remains poor, but outcomes in those receiving maximal treatment match those from clinical trials. However, most patients do not receive maximal treatment, and so the easiest route to improving outcomes may be optimise delivery of treatment in the 65% of patients who receive sub-maximal treatment. More information on https://blogs.imperial.ac.uk/gliocova
The Experiences of People With Glioma and Their Caregivers: Living With Uncertainty and Long Term Consequences (COBra Study)
Authors: Elin Baddeley, Ameeta Retzer, Stephanie Sivell, Kathy Seddon, Helen Bulbeck, Annmarie Nelson, Melanie Calvert, Robin Grant, Richard Adams, Colin Watts, Olalekan Lee Aiyegbusi, Samantha Cruz Rivera, Pamela Kearns, Linda Dirven, Anthony Byrne
Journal: Neuro-Oncology (2022)

Abstract AIMS Glioma, the most common primary brain tumour, has variable survival rates. Existing evidence describes detriment to quality of life from persistent symptoms/side effects, functional loss and feelings of disconnection, particularly in glioblastoma; however, there remains limited focus on the experience of longer-term survivors. This study aimed to ascertain the lived experience of people with glioma and their caregivers, part of a larger study identifying outcomes for a core outcome set for use in glioma trials (COBra study). METHOD Semi-structured interviews with UK glioma patients, or patient-caregiver dyads, analysed using Thematic Analysis. RESULTS Nineteen interviews were undertaken. Patients and caregivers described living with uncertainty long after diagnosis and treatment, including prognostic uncertainty and anxiety surrounding recurrence and worsening symptoms. Patients described an inability to plan long-term, struggling to return to normal activities, either due to progressive tumour symptoms, and/or treatment side effects. Long-term physical and psychological side effects were highly impactful; patients felt left alone to cope, with support following treatment dropping off rapidly. Patients/caregivers sought self-directed ways to cope, focusing on routine and achieving some normality. However, the physical and neurological effects of glioma and its treatment affected all aspects of daily life and social interactions, impacting on sense of wellbeing and quality of life. CONCLUSION People with glioma, and their caregivers, struggle with loss of normality and living with uncertainty long after diagnosis. They proactively engage in self-directed approaches towards mitigating these effects, but experience gaps in support after treatment finishes. Clinical follow up should target these aspects of assessment and intervention.
The Impact of Molecular Analysis on Patient Waiting Time: A Neurosurgical Audit
Authors: Jeremy Easow Maducolil, Mohammad Arish Mustafa, Wallis Hayes, Amanda Williams, Piyali Pal, Nitika Rathi, Andrew Brodbelt
Journal: Neuro-Oncology (2022)

Abstract AIMS The 2021 WHO classification includes molecular characterizations to a much greater degree. Molecular markers play an important role in deciding treatment choice and predicting prognosis. Molecular markers are often performed in separate laboratories. This has led to concerns about the amount of time taken to get further molecular markers and the delay in diagnosis. Therefore our aim was to determine the waiting time for molecular markers to be returned from the lab following surgery. METHOD We retrospectively collected data for patients who had molecular analysis conducted in 2020 for gliomas at The Walton Centre, Liverpool. Descriptive statistics were conducted using SPSS V27.0. RESULTS 182 patients were included. 130 patients waited &amp;lt;4 weeks, 46 patients &amp;gt;4 weeks, and 6 patients &amp;gt;8 weeks for molecular marker results. The median waiting time was 21 days (range: 11-219, IQR: 17.00-31.00). For patients who waited &amp;gt;4 weeks and &amp;gt;8 weeks, there were 7 WHO Grade I, 7 Grade II, 2 Grade III, and 26 Grade IV tumours. The median time taken between surgery and treatment to begin was 15 working days (range: 7-86, IQR: 12.00- 25.00). M-array took the longest time to return with a median of 63.5 days (range: 48-93, IQR: 60.00-80.00). Following which was NGS results which took a median of 32 days (range: 21-219, IQR: 27.00-40.00) CONCLUSION Most patients received their results in less than 4 weeks, however nearly a third had a waiting time of greater than 4 weeks. Reasons for delays need to be explored further to allow for quicker intervention from the MDT.
Extent of MGMT Promoter Methylation Modifies the Effect of Temozolomide on Overall Survival in Patients with Glioblastoma: A Regional Cohort Study
Authors: Michael T C Poon, Shivank Keni, Vineeth Vimalan, Chak Ip, Colin Smith, Sara Erridge, Christopher Weir, Paul Brennan
Journal: Neuro-Oncology (2022)

Abstract AIMS MGMT methylation in glioblastoma predicts response to temozolomide but dichotomizing methylation status may mask the true prognostic value of quantitative MGMT methylation. This study evaluated whether extent of MGMT methylation interacts with the effect of temozolomide on overall survival. METHOD We included consecutive glioblastoma patients aged ≥16 years diagnosed (April 2012–May 2020) at a neuro-oncology center. All patients had quantitative MGMT methylation measured using pyrosequencing. Those with MGMT methylated tumors were stratified into high and low methylation groups based on a cut-off using Youden index on 2-year survival. Our accelerated failure time survival models included extent of MGMT methylation, age, postoperative Karnofsky performance score, extent of resection, temozolomide regimen, and radiotherapy. RESULTS There were 414 patients. Optimal cut-off point using Youden index was 25.9% MGMT methylation. The number of patients in the unmethylated, low and high methylation groups was 223 (53.9%), 81 (19.6%), and 110 (26.6%), respectively. In the adjusted model, high (hazard ratio [HR] 0.60, 95% confidence intervals [CI] 0.46– 0.79, P=0.005) and low (HR 0.67, 95% CI 0.50–0.89, P&amp;lt;0.001) methylation groups had better survival compared to unmethylated group. There was no evidence for interaction between MGMT methylation and completed temozolomide regimen (interaction term for low methylation P=0.097; high methylation P=0.071). This suggests no strong effect of MGMT status on survival in patients completing temozolomide regimen. In patients not completing the temozolomide regimen, higher MGMT methylation predicted better survival (interaction terms P&amp;lt;0.001). CONCLUSION Quantitative MGMT methylation may provide additional prognostic value. This is important when assessing clinical and research therapies.